This invention relates to a process and composition for neutralizing heparin and more particularly to a process and composition for neutralizing heparin administered to a patient.
Heparin is a mucopolysaccharide composed mainly of alternating structures of D-glucosamine and L-iduronic acid with a molecular weight ranging between 8000 and 15,000 daltons. It has a strong negative charge. The blood anticoagulating effect of heparin is believed due to blocking the elaboration of prothrombin or inhibiting, in the presence of a plasma cofactor, the action of thrombin and the conversion of fibrinogen to fibrin.
Heparin has found numerous applications in the area of hemodialysis pulmonary embolism disseminated intravascular coagulation, peripheral vascular surgery, cardiac surgery, transplantation and autotransfusion. Extracorporeal medical devices, e.g., artificial kidney, pump-oxygenator, profused with blood have been an effective part of therapy for many years. These devices all rely on systemic heparinization to provide the blood compatibility. Despite continuous efforts to improve anticoagulation techniques, many patients still develop coagulation abnormalities with the use of these devices. Devices such as the membrane oxygenator which utilize even longer profusion times, the drawbacks of systemic heparinization are multiplied. A number of approaches have been attempted to solve this problem. These include: administration of compounds, development of heparin substitutes, bonding heparin or other substances to the extracoporeal device and development of new blood-compatible material for construction of the extracorporeal device. Although the approach has led to some improvements, control of blood heparin levels remains a serious problem. Heparin usage has permitted control of coagulation and prevention of active clotting but can cause severe complications. The most frequent complication of heparin therapy is hemorrhage. The severity of the hemorrhage may vary from mild mucosal oozing to massive intracranial, gastrointestinal and intrathoracic bleeding. The incidence of hemorrhage resulting from heparization is about 8-33%. Coagulation abnormalities have increated drastically with the recent developments of long-term pulmonary support with membrane oxygenators. In addition to hemorrhage, there are a number of other complications associated with heparinization, particularly when the drug is administered over a long period. Some of these complications include alopecia, interference with bone repair, leading in some cases, to severe decalcifying bone disease.
Because of the complications associated with heparin therapy, the need exists to neutralize heparin, thereby destroying its anti-coagulant activity. The primary treatment utilized in the neutralization of heparin has been combining it with a positively charged drug. The clinical choice for this purpose has been protamine sulfate. The administration of protamine to neutralize heparin, however, may produce hypotension and also can produce a rise in pulmonary artery pressure, a fall in lung compliance and a reduction in arterial oxygen tension.
Complications associated with heparin therapy and its neutralization have caused considerable attention to be focused on devising means for permitting extracorporeal blood flow without heparinization. One approach is to utilize heparin substitutes. However, heparin is still the anti-coagulant suitable for routine use in extracorporeal circuits. A major effort has been made to develop new extracorporeal surfaces or methods of coating commonly used surfaces with heparin or other additives. The most common of these approaches has been the binding of heparin itself to the extracorporeal surface by means of covalent bonding or by a non-specific means such as ionic bond. Another approach is to include the binding of hydro gels, chemical attachment of urokinase, the use of negatively charged materials, new bio-materials and coating with substances such as silicone. In spite of these efforts, it seems clear that heparinization will continue to be important; because of the complications that heparin can cause, it would be desirable to have an effective means for controlling its concentration.